1. Field of the Invention
The present invention relates to isothiazole derivatives with antipyretic, analgesic and antiphlogistic effect, or nontoxic salts of the isothiazole derivatives, process for the preparation thereof, and pharmaceutical composition including the same as an effective component.
2. Background of the Related Art
Most of non-steroid anti-inflammatory drugs represent actions such as anti-inflammation, analgesic, and antipyretic activity by inhibiting the enzymatic activity of cyclooxygenase or prostaglandin G/H synthase. In addition, they can suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. Firstly, only cyclooxygenase-1 (COX-1), found in cow as a constitutional enzyme, was known. But recently, cyclooxygenase-2 is identified to be discriminated clearly from cyclooxygenase-1 and can be provoked easily by mitogen, endotoxin, hormones, growth factors, cytokines and the like.
Prostaglandins have various pathological and physiological functions. Precisely, cyclooxygenase-1 as a constitutional enzyme participates in the secretion of basic endogenous prostaglandin and plays an important role in physiological aspects such as stomach homeostasis, renal blood circulation and so on. On the other hand, cyclooxygenase-2 is induced by inflammatory factors, hormones, growth factors, cytokines and the like, and thus plays an important role in pathological effects of prostaglandin. Therefore, selective inhibitors against cyclooxygenase-2 are expected to have no side effect on account of the functional mechanism compared with the anti-inflammatory drugs such as conventional non-steroid agents and to represent actions such as antiphlogistic, analgesic and antipyretic activity. Furthermore, it is estimated to suppress the uterine contraction induced by hormones and the cell proliferation in several kinds of cancers. Especially, it probably has a few side effects such as gastrointestinal toxicity, renal toxicity and the like. Also, it is assumed to prevent the synthesis of contractive prostanoids, and thus inhibit the contraction of smooth muscle induced by the prostanoid. Hence, it can be applied usefully to treat a premature birth, dysmenorrhea, asthma and several diseases associated with eosinophilic leukocytes. Besides, it can be widely exploited to cure osteoporosis, glaucoma, large intestine cancer, prostatic carcinoma and athymia, which has been disclosed in many references, especially the usefulness of selective inhibitors against cyclooxygenase-2 (References: John Vane, “Towards a better aspirin” in Nature, Vol.367, p215-216, 1994; Bruno Battistini, Regina Botting and Y. S. Bakhle, “COX-1 and COX-2: Toward the Development of More Selective NSAIDs” in Drug News and Perspectives, Vol.7, p501-512, 1994; Urology, Vol.58, p127, 2001; David B. Reitz and Karen Seibert, “Selective Cyclooxygenase Inhibitors” in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, p179-188, 1995).
The selective inhibitors against cyclooxygenase-2 have been reported to have various structure forms. Among these, the diaryl heterocycle structure, namely a tricyclic system, has been studied most frequently and exploited to construct a lot of candidate substances. In this structure, it is essential that sulfonamide or methanesulfone group exist onto one phenyl group.
U.S. Pat. No. 5,466,823 disclosed celecoxib, the compound of the following formula 36. The celecoxib is a substituted pyrazolyl benzonesulfonamide derivative. 
WO Pub. No. 95/00501 disclosed rofecoxib, the compound of the following formula 37. The rofecoxib has the same diaryl heterocycle structure as celecoxib of the formula 36, but the heterocycle structure is furanone structure. 
U.S. Pat. No. 5,633,272 disclosed valdecoxib, the compound of the following formula 38. The valdecoxib has the same phenyl sulfonamide structure as celecoxb of the formula 37, but the heterocycle structure is isoxazole structure. 
The forgoing compounds of the formula 36, 37 and 38 have antiphlogistic and analgesic effect without side effects comparing with the conventional non-steroid anti-inflammatory drugs as a selective cyclooxygenase-2 inhibitor.